High-resolution retinal imaging can significantly improve the quality of diagnosis, disease progression tracking and assessment of therapy in a broad range of retinal diseases including, for example, retinal degenerations (retinitis pigmentosa), macular telangiectasis, macular dystrophies, age-related macular degeneration (AMD), and inflammatory diseases. Some of these diseases are prevalent (AMD afflicts 12% of the population aged 80+, and retinitis pigmentosa is the most common cause of blindness/low-vision in adults 20-60 years old) and progress slowly, which drives the need for a cost-effective imaging solution that can be broadly deployed for screening and tracking purposes. The availability of new therapeutics further drives this need for a cost-effective imaging solution since the ability to discern the exact impact of the drugs at the cell level is highly useful in informing clinicians about the course of treatments.
Accounting for the numerical aperture of the eye as set by a nominal pupil diameter of 6 mm, an imaging system should be able to focus light to a diffraction-limited spot of size of 1.9 microns on the retina (630 nm wavelength) except that aberrations in the eye actually result in a much poorer focus spot. Conventional retinal imaging techniques correct for aberrations by including a corrective physical optical arrangement to compensate for the aberrations before acquiring images. This conventional strategy is the basis of the adaptive optics (AO) work that was first started in astronomy and that has been applied to ophthalmic imaging systems, in particular confocal scanning laser ophthalmoscopes (cSLO). Conventional adaptive optics scanning laser ophthalmoscopes (AOSLO) have significant limitations that have hindered their broad clinical use. First, the field of view of AO corrected images tends to be very small oftentimes only 1 degree in size. Since retinal diseases can occupy large portions of the macula and retina, conventional AO techniques requires multiple images to be obtained and montaged and increases the acquisition time. Long acquisition times are generally impractical for routine clinical use, especially with eye motion from the patient. This requires high-speed tracking systems since AO requires feedback to keep the aberration correction current. Second, the uneven topology of many retinal diseases presents a major challenge because regions not in the focal plane of the optics will appear out of focus. Third, despite reductions in the cost of certain components, such as deformable mirrors, these conventional systems still remain expensive, limiting their commercial feasibility.
Fourier ptychography is a resolution-enhancement imaging technique that can be applied to a conventional 4f optical arrangement to increase the system's effective numerical aperture, remove the inherent optical aberrations in the system, and allow for quantitative phase measurement of a sample. Details of the Fourier ptychography imaging technique are described in G. Zheng, R. Horstmeyer and C. Yang, “Wide-field, high-resolution Fourier ptychographic microscopy,” Nature Photonics, 2013, which is hereby incorporated by reference in its entirety. Fourier ptychography typically uses the aberration characterization technique referred to as the Embedded Pupil Function Recovery (EPRY) method, which is described in X. Ou, G. Zheng and C. Yang, “Embedded pupil function recovery for Fourier ptychographic microscopy,” Optics Express, 2014, which is hereby incorporated by reference in its entirety. The EPRY method is based on images acquired using coherent illumination, such as from light-emitting diodes (LEDs) placed sufficiently far away from the sample or a collimated laser beam, to provide coherent illumination with a consistent beam profile to the sample at varied illumination angles sequentially (i.e. at different sample times). The EPRY method uses the sequence of images captured when the sample is illuminated by various angles with coherent illumination to reconstruct the system's aberration function, also known as the pupil function, while simultaneously reconstructing the sample's complex function. However, it is difficult to deliver a consistent illumination beam at varied illumination angles to a sample if the path between the coherent illumination source and the sample is under the influence of unknown refraction effects. For example, if one were to image the retinal surface of a human eye in-vivo, the coherent illumination needs to be provided via the cornea, lens, and the vitreous humor inside the eye before reaching the retinal surface. Because it is very hard to know the exact refractive error caused by these elements, the illumination profile reaching the retinal surface is not usually known and the EPRY technique cannot usually be applied directly to reconstruct the pupil function of the eye without some error introduced. In another example, EPRY cannot usually be applied directly to characterize the aberrations of a digital camera when taking pictures of natural scenes because it is not practical to deliver coherent illumination at varied angles to natural scenes being imaged.